Pharmacological and Toxicological Implications of Multiple Cytochromes P-450

The Influence of Dietary Protein and Carbohydrate on the Principal Oxidative Biotransformations of Estradiol in Normal Subjects*

“…There are multiple forms of hepatic cytochrome P-450, which have different but overlapping substrate specificities, and these cytochrome P-450 isozymes are influenced to different degrees by various chemical inducers (14,18,19). It is likely that the protein and/or carbohydrate content of the human diet will not have the same influence on all cytochrome P-450-dependent enzyme activities.…”

Pharmacogenetic Perspectives: Genes, Drugs and Disease

“…In this context, it should be recalled that lack of follow-up of Shahidi's paper in 1967 on sibs with phenacetin toxicity (52) delayed by a decade full recognition of the genetic locus now known to be responsible for the debrisoquine-sparteine polymorphism. Efforts to elucidate the molecular basis of this polymorphism have given impetus to the development of human liver banks to characterize the microsoma1 cytochrome P-450 isozymes of different subjects and populations (48)(49)(50). While this approach could theoretically lead to the discovery of new polymorphisms of drug oxidation, the history of pharmacogenetics indicates that such discoveries in humans emerged from observations made in uivo, not in uitro.…”

“…Finally, most hepatic isozymes of cytochrome P-450 are readily induced by numerous drugs; individual isozymes generally exhibit distinctive patterns of enhancement, each responding somewhat differently from others (50). While PM and EM phenot.ypes both showed induced debrisoquine metabolism after pretreatment with phenobarbital, antipyrine or rifampicin, sparteine metabolism was unaffected (46); this observation suggests not only participation of a different cytochrome P-450 isozyme for sparteine and debrisoquine but an unusual resistance to induction of the isozyme that biotransforms sparteine.…”

“…Microsomes prepared from these livers failed to metabolize not only debrisoquine but also many other drugs associated with the debrisoquine polymorphism, but total cytochrome P-450 was not reduced and electrophoresis disclosed no obvious qualitative change in the complement of proteins. However, a fundamental principle of drug metabolism holds that most drugs biotransformed by multiple pathways of hepatic oxidation are catalyzed by at least several cytochrome P-450 isozymes, not just one (50). In addition, a single cytochrome P-450 isozyme is thought to catalyze closely related biochemical functions, i.e., to exhibit stereo and regioselectivity toward certain substrates.…”

Toxicokinetics: Biotransformation of Toxicants

“…Another important property of the cytochrome P450 superfamily is its inducibility by exogenous and endogenous compounds (Conney, 1967(Conney, , 1982Gustafsson et al, 1983;Porter and Coon, 1991). Enzyme induction can be defined as the increase in the biosynthesis of catalytically active enzyme following exposure of the organism to chemical agents or physiological conditions.…”